Bcma-directed cellular immunotherapy compositions and methods

Abstract

Provided for herein in several embodiments are anti-BCMA binding moieties. These anti-BCMA binding moieties may be used in BCMA-directed chimeric antigen receptors (CARs). Also disclosed herein are immune cell-based compositions comprising the anti-BCMA binding moieties and BCMA-directed CARs. In several embodiments, the immune-cell based compositions also target an additional tumor marker and/or an additional epitope of BCMA. In several embodiments, the BCMA-directed CAR is expressed in a Natural Killer cell. In several embodiments, combinations of BCMA-CAR-expressing NK cells are administered in conjunction with, for example CAR-expressing NK cells and/or CAR-expressing T cells that are directed to an additional cancer marker and/or an additional epitope of BCMA. Also provided for herein are methods and uses of the chimeric antigen receptors in immunotherapy.

1 - 87 . (canceled) 
     
     
         88 . An anti-BCMA binding moiety comprising a heavy chain variable region (VH) comprising a HCDR1, a HCDR2, and a HCDR3, and a light chain variable region (VL) comprising a LCDR1, a LCDR2, and a LCDR3, wherein the VH comprises the HCDR1, the HCDR2, and the HCDR3 contained within the VH amino acid sequence set forth in any one of SEQ ID NOS:260-285 and 1582-1600; and the VL comprises the LCDR1, the LCDR2, and the LCDR3 contained within the VL amino acid sequence set forth in any one of SEQ ID NOS:541-566 and 1677-1695. 
     
     
         89 . The anti-BCMA binding moiety of  claim 88 , wherein the VH comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOS:260-285 and 1582-1600, and the VL comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOS:541-566 and 1677-1695. 
     
     
         90 . The anti-BCMA binding moiety of  claim 88 , wherein the VH comprises the amino acid sequence set forth in any one of SEQ ID NOS:260-285 and 1582-1600, and the VL comprises the amino acid sequence set forth in any one of SEQ ID NOS:541-566 and 1677-1695. 
     
     
         91 . The anti-BCMA binding moiety of  claim 88 , wherein:
 (a) the VH comprises the HCDR1, the HCDR2, and the HCDR3 contained within the VH amino acid sequence set forth in SEQ ID NO:268, and the VL comprises the LCDR1, the LCDR2, and the LCDR3 contained within the VL amino acid sequence set forth in SEQ ID NO:549;   (b) the VH comprises the HCDR1, the HCDR2, and the HCDR3 contained within the VH amino acid sequence set forth in SEQ ID NO:270, and the VL comprises the LCDR1, the LCDR2, and the LCDR3 contained within the VL amino acid sequence set forth in SEQ ID NO:551;   (c) the VH comprises the HCDR1, the HCDR2, and the HCDR3 contained within the VH amino acid sequence set forth in SEQ ID NO:1600, and the VL comprises the LCDR1, the LCDR2, and the LCDR3 contained within the VL amino acid sequence set forth in SEQ ID NO:1695; or   (d) the VH comprises the HCDR1, the HCDR2, and the HCDR3 contained within the VH amino acid sequence set forth in SEQ ID NO:1586, and the VL comprises the LCDR1, the LCDR2, and the LCDR3 contained within the VL amino acid sequence set forth in SEQ ID NO:1681.   
     
     
         92 . The anti-BCMA binding moiety of  claim 88 , wherein:
 (a) the VH comprises an amino acid sequence having at least 90% sequence identity to the VH amino acid sequence set forth in SEQ ID NO:268, and the VL comprises an amino acid sequence having at least 90% sequence identity to the VL amino acid sequence set forth in SEQ ID NO:549;   (b) the VH comprises an amino acid sequence having at least 90% sequence identity to the VH amino acid sequence set forth in SEQ ID NO:270, and the VL comprises an amino acid sequence having at least 90% sequence identity to the VL amino acid sequence set forth in SEQ ID NO:551;   (c) the VH comprises an amino acid sequence having at least 90% sequence identity to the VH amino acid sequence set forth in SEQ ID NO:1600, and the VL comprises an amino acid sequence having at least 90% sequence identity to the VL amino acid sequence set forth in SEQ ID NO:1695; or   (d) the VH comprises an amino acid sequence having at least 90% sequence identity to the VH amino acid sequence set forth in SEQ ID NO:1586, and the VL comprises an amino acid sequence having at least 90% sequence identity to the VL amino acid sequence set forth in SEQ ID NO:1681.   
     
     
         93 . The anti-BCMA binding moiety of  claim 88 , wherein:
 (a) the VH comprises the amino acid sequence set forth in SEQ ID NO:268, and the VL comprises the amino acid sequence set forth in SEQ ID NO:549;   (b) the VH comprises the amino acid sequence set forth in SEQ ID NO:270, and the VL comprises the amino acid sequence set forth in SEQ ID NO:551;   (c) the VH comprises the amino acid sequence set forth in SEQ ID NO:1600, and the VL comprises the amino acid sequence set forth in SEQ ID NO:1695; or   (d) the VH comprises the amino acid sequence set forth in SEQ ID NO:1586, and the VL comprises the amino acid sequence set forth in SEQ ID NO:1681.   
     
     
         94 . The anti-BCMA binding moiety of  claim 88 , wherein the anti-BCMA binding moiety is a single-chain variable fragment (scFv), a Fv, a Fab, or a F(ab′)2. 
     
     
         95 . The anti-BCMA binding moiety of  claim 88 , wherein the VH and VL are joined by a linker comprising the amino acid sequence set forth in SEQ ID NO:1388 or 2388. 
     
     
         96 . The anti-BCMA binding moiety of  claim 88 , wherein the anti-BCMA binding moiety is a single-chain variable fragment (scFv) comprising the amino acid sequence set forth in any one of SEQ ID NOS:593-618 or 671-696. 
     
     
         97 . An anti-BCMA binding moiety comprising a first heavy chain variable region (VHH1), wherein the VHH1 comprises a HCDR1, a HCDR2, and a HCDR3 contained within the VHH1 amino acid sequence set forth in any one of SEQ ID NOS:3255-3277. 
     
     
         98 . The anti-BCMA binding moiety of  claim 97 , wherein the VHH1 comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOS:3255-3277. 
     
     
         99 . The anti-BCMA binding moiety of  claim 97 , wherein:
 (a) the VHH1 comprises the HCDR1, the HCDR2, and the HCDR3 contained within the VHH1 amino acid sequence set forth in SEQ ID NO:3262;   (b) the VHH1 comprises the HCDR1, the HCDR2, and the HCDR3 contained within the VHH1 amino acid sequence set forth in SEQ ID NO:3263;   (c) the VHH1 comprises the HCDR1, the HCDR2, and the HCDR3 contained within the VHH1 amino acid sequence set forth in SEQ ID NO:3264;   (d) the VHH1 comprises the HCDR1, the HCDR2, and the HCDR3 contained within the VHH1 amino acid sequence set forth in SEQ ID NO:3265;   (e) the VHH1 comprises the HCDR1, the HCDR2, and the HCDR3 contained within the VHH1 amino acid sequence set forth in SEQ ID NO:3271; or   (f) the VHH1 comprises the HCDR1, the HCDR2, and the HCDR3 contained within the VHH1 amino acid sequence set forth in SEQ ID NO:3273.   
     
     
         100 . The anti-BCMA binding moiety of  claim 97 , further comprising a second heavy chain variable region (VHH2), wherein the VHH2 comprises a HCDR1, a HCDR2, and a HCDR3 contained within the VHH2 amino acid sequence set forth in any one of SEQ ID NOS:3255-3277. 
     
     
         101 . The anti-BCMA binding moiety of  claim 100 , wherein the VHH2 comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOS:3255-3277. 
     
     
         102 . The anti-BCMA binding moiety of  claim 100 , wherein the anti-BCMA binding moiety comprises the amino acid sequence set forth in any one of SEQ ID NOS:3324-3346. 
     
     
         103 . A BCMA-directed chimeric antigen receptor (CAR) comprising:
 (a) the anti-BCMA binding moiety of  claim 88 ;   (b) a hinge domain;   (c) a transmembrane domain; and   (d) an intracellular signaling domain comprising a co-stimulatory subdomain and a CD3ζ subdomain.   
     
     
         104 . The BCMA-directed CAR of  claim 103 , wherein the co-stimulatory subdomain comprises an OX40 subdomain, a CD28 subdomain, or a 4-1BB subdomain. 
     
     
         105 . A polynucleotide encoding the anti-BCMA binding moiety of  claim 88 . 
     
     
         106 . A polynucleotide encoding the anti-BCMA binding moiety of  claim 97 . 
     
     
         107 . A vector comprising the polynucleotide of  claim 105 . 
     
     
         108 . An immune cell comprising the BCMA-directed CAR of  claim 88 . 
     
     
         109 . The immune cell of  claim 108 , wherein the immune cell is a natural killer (NK) cell or T cell. 
     
     
         110 . A composition comprising a plurality of the immune cells of  claim 108 . 
     
     
         111 . A method for treating a subject having a cancer, the method comprising administering the composition of  claim 110  to a subject having a cancer. 
     
     
         112 . The method of  claim 111 , wherein the cancer is multiple myeloma.